Evolution and development of the adelphophagic, intracapsular Schmidt's larva of the nemertean Lineus ruber.
The life cycle of many animals includes a larval stage, which has diversified into an astonishing variety of ecological strategies. The Nemertea is a group of spiralians that exhibits a broad diversity of larval forms, including the iconic pilidium. A pelagic planktotrophic pilidium is the ancestral form in the Pilidiophora, but several lineages exhibit deviations of this condition, mostly as a transition to pelagic lecithotrophy. The most extreme case occurs, however, in the Pilidiophoran Lineus ruber, which exhibits an adelphophagic intracapsular pilidium, the so-called Schmidt's larva. We combined confocal laser scanning microscopy and gene expression studies to characterize the development and metamorphosis of the Schmidt's larva of L. ruber. The larva forms after gastrulation, and comprises a thin epidermis, a proboscis rudiment and two pairs of imaginal discs from which the juvenile will develop. The cells internalized during gastrulation form a blind gut and the blastopore gives rise to the mouth of the larva and juvenile. The Schmidt's larva eats other siblings that occupy the same egg capsule, accumulating nutrients for the juvenile. A gradual metamorphosis involves the differentiation of the juvenile cell types from the imaginal discs and the shedding of the larval epidermis. The expression of evolutionarily conserved anterior (foxQ2, six3/6, gsc, otx), endomesodermal (foxA, GATA456-a, twi-a) and posterior (evx, cdx) markers demonstrate that the juvenile retains the molecular patterning of the Schmidt's larva. After metamorphosis, the juveniles stay over 20 days within the egg masses, until they are fully mature and hatch. The evolution of the intracapsular Schmidt's larva involved the loss of the typical feeding structures of the planktotrophic pilidium and a precocious formation of the imaginal discs, as also observed in other pelagic lecithotrophic forms. However, no special adaptations are observed related to adelphophagy. As in planktotrophic pilidium, the molecular mechanism patterning the juvenile is only active in the imaginal discs and not during the early development of the larva, suggesting two separate molecular programs during nemertean embryogenesis. Our results illuminate the diversification of larval forms in the Pilidiophora and Nemertea, and thus on the developmental mechanisms underlying metazoan larval evolution.


Optical parametric oscillation in periodically poled lithium niobate driven by a diode-pumped Q-switched erbium fiber laser.
We describe what is to our knowledge the first nanosecond periodically poled lithium niobate (PPLN) optical parametric oscillator (OPO) driven by a fiber laser. The source was frequency doubled by a PPLN sample before pumping a second, 20-mm-long, PPLN crystal. The OPO threshold was <10muJ, with pump depletions of as much as 45% and a tunable signal range of 945-1450 nm (1690-4450-nm idler range). We demonstrated 130-nm signal tuning by varying the pump wavelength and doubling crystal's temperature. Also, we achieved 15-nm tuning with all crystals at a constant temperature. The results demonstrate the potential of the fiber laser:PPLN combination for practical, versatile, and tunable sources.


DNase I-hypersensitive sites enhance alpha1(I) collagen gene expression in hepatic stellate cells.
Liver fibrosis is characterized by a dramatic increase in the expression of type I collagen. Several deoxyribonuclease (DNase) I-hypersensitive sites (HS) have been located in the distal 5'-flanking region of the alpha1(I) collagen gene that are specific to collagen-producing cells. To assess the role of the DNase I-HS in regulating alpha1(I) collagen gene expression in hepatic stellate cells (HSCs), 3 transgenic mouse lines expressing collagen-alpha1(I) reporter genes were used (Krempen et al. Gene Expr 1999;8:151-163). The pCol9GFP transgene contains the collagen gene promoter (-3122 to +111) linked to the green fluorescent protein (GFP) reporter gene. The pCol9GFP-HS4,5 transgene contains HS4,5 and pColGFP-HS8,9 contains HS8,9 positioned upstream of the collagen promoter in pCol9GFP. HSCs isolated from transgenic mice containing pCol9GFPHS4,5 and pColGFP-HS8,9 showed earlier and higher GFP expression patterns than HSCs isolated from pCol9GFP mice. HSCs from pCol9GFP-HS4,5 showed the highest levels of GFP expression and culture-induced expression correlated with induction of the endogenous alpha1(I) collagen gene. After CCl(4) administration, pCol9GFP-HS4,5 mice showed increased GFP expression compared with pCol9GFP mice in both whole liver extracts and isolated HSCs. Several sites for DNA-protein interactions in both HS4 and HS5 were identified that included a binding site for activator protein 1. In conclusion, DNase I-HS4,5 enhance expression of the alpha1(I) collagen gene promoter in HSCs both in vitro and in vivo after a fibrogenic stimulus. The collagen-GFP transgenic mice provide a convenient and reliable model system to investigate the molecular mechanisms controlling increased collagen expression during fibrosis.


Associations of CAHPS Composites With Global Ratings of the Doctor Vary by Medicare Beneficiaries' Health Status.
Care coordination among health care providers is essential for high-quality care and it is strongly associated with overall ratings of doctors. Care coordination may be especially important for sicker and chronically ill patients because of the multiple providers involved in their care. This study examines whether the association of care coordination with global ratings of one's personal doctor varies by number of chronic conditions and self-rated health. We used nationally representative Medicare Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey data to evaluate care coordination, doctor communication, getting needed care, getting care quickly, count of 6 chronic conditions (angina, cancer, chronic obstructive pulmonary disease, diabetes, heart attack, stroke), self-rated general health (5-point scale, poor to excellent, scored linearly), and interactions among them as predictors of the CAHPS global rating of personal doctor (scored 0-100 with 100 being best possible personal doctor) using linear regression models. The analytic sample included 242,871 Medicare fee-for-service and managed care beneficiaries in 2013: 56% female; 14% 18-64, 47% 65-74, 27% 75-84, and 11% 85 and older; and 48% high school education or less. The CAHPS composites (of care coordination, doctor communication, getting needed care, and getting care quickly) and number of chronic conditions were significantly positively associated with ratings of personal doctor (P<0.05). Care coordination and doctor communication had a stronger association with positive ratings of the personal doctor among those with worse self-rated health (P<0.001). Results were consistent with the hypothesis that patients in worse health weigh care coordination more heavily in global physician assessments than patients in better health. Emphasis on improving care coordination, especially for patients in poorer health, may improve patients' overall assessments of their providers. The study provides further evidence for the importance of care coordination experiences in the era of patient-centered care.


Complex genomic rearrangements in the dystrophin gene due to replication-based mechanisms.
Genomic rearrangements such as intragenic deletions and duplications are the most prevalent type of mutations in the dystrophin gene resulting in Duchenne and Becker muscular dystrophy (D/BMD). These copy number variations (CNVs) are nonrecurrent and can result from either nonhomologous end joining (NHEJ) or microhomology-mediated replication-dependent recombination (MMRDR). We characterized five DMD patients with complex genomic rearrangements using a combination of MLPA/mRNA transcript analysis/custom array comparative hybridization arrays (CGH) and breakpoint sequence analysis to investigate the mechanisms for these rearrangements. Two patients had complex rearrangements that involved microhomologies at breakpoints. One patient had a noncontiguous insertion of 89.7 kb chromosome 4 into intron 43 of DMD involving three breakpoints with 2-5 bp microhomology at the junctions. A second patient had an inversion of exon 44 flanked by intronic deletions with two breakpoint junctions each showing 2 bp microhomology. The third patient was a female with an inherited deletion of exon 47 in DMD on the maternal allele and a de novo noncontiguous duplication of exons 45-49 in DMD and MID1 on the paternal allele. The other two patients harbored complex noncontiguous duplications within the dystrophin gene. We propose a replication-based mechanisms for all five complex DMD rearrangements. This study identifies additional underlying mechanisms in DMD, and provides insight into the molecular bases of these genomic rearrangements.


A compilation of national plans, policies and government actions for rare diseases in 23 countries.
Previous studies have focused on the comparison of specific laws among multiple countries and regions; for example, laws related to facilitating treatments with orphan drugs or laws seeking to address the multiple needs of patients with rare diseases. The purpose of this scoping review is to examine and compare published reports on national plans, polices and legislation related to all rare diseases in different countries. We also examine strategies or programs that countries may have for these diseases. Articles were obtained from journals and books published between January 1, 2000, through December 15, 2017. Reports from the grey literature (documents issued by government and private organizations) were included if they were available on the internet. The databases used were Google and Google Scholar, PubMed, and the websites of Orphanet and the National Organization for Rare Disorders (NORD). We obtained information on 23 countries. Among these countries, the way in which rare diseases were defined varied from having similar definitions to no definition. Multinational programs supported by common or similar laws are likely to have a greater impact on rare diseases than single country programs.


Nephromyces Encodes a Urate Metabolism Pathway and Predicted Peroxisomes, Demonstrating That These Are Not Ancient Losses of Apicomplexans.
The phylum Apicomplexa is a quintessentially parasitic lineage, whose members infect a broad range of animals. One exception to this may be the apicomplexan genus Nephromyces, which has been described as having a mutualistic relationship with its host. Here we analyze transcriptome data from Nephromyces and its parasitic sister taxon, Cardiosporidium, revealing an ancestral purine degradation pathway thought to have been lost early in apicomplexan evolution. The predicted localization of many of the purine degradation enzymes to peroxisomes, and the in silico identification of a full set of peroxisome proteins, indicates that loss of both features in other apicomplexans occurred multiple times. The degradation of purines is thought to play a key role in the unusual relationship between Nephromyces and its host. Transcriptome data confirm previous biochemical results of a functional pathway for the utilization of uric acid as a primary nitrogen source for this unusual apicomplexan.


Improving causal inferences in risk analysis.
Recent headlines and scientific articles projecting significant human health benefits from changes in exposures too often depend on unvalidated subjective expert judgments and modeling assumptions, especially about the causal interpretation of statistical associations. Some of these assessments are demonstrably biased toward false positives and inflated effects estimates. More objective, data-driven methods of causal analysis are available to risk analysts. These can help to reduce bias and increase the credibility and realism of health effects risk assessments and causal claims. For example, quasi-experimental designs and analysis allow alternative (noncausal) explanations for associations to be tested, and refuted if appropriate. Panel data studies examine empirical relations between changes in hypothesized causes and effects. Intervention and change-point analyses identify effects (e.g., significant changes in health effects time series) and estimate their sizes. Granger causality tests, conditional independence tests, and counterfactual causality models test whether a hypothesized cause helps to predict its presumed effects, and quantify exposure-specific contributions to response rates in differently exposed groups, even in the presence of confounders. Causal graph models let causal mechanistic hypotheses be tested and refined using biomarker data. These methods can potentially revolutionize the study of exposure-induced health effects, helping to overcome pervasive false-positive biases and move the health risk assessment scientific community toward more accurate assessments of the impacts of exposures and interventions on public health.


The B cell antigen receptor of class IgD induces a stronger and more prolonged protein tyrosine phosphorylation than that of class IgM.
Most mature B lymphocytes coexpress two classes of antigen receptor, immunoglobulin (Ig)M and IgD. The differences in the signal transduction from the two receptors are still a matter of controversy. We have analyzed B cell lines expressing IgM or IgD antigen receptors with the same antigen specificity. Cross-linking of these receptors with either antigen, or class-specific antibodies, results in the activation of protein tyrosine kinases and the phosphorylation of the same substrate proteins. The kinetic and the intensity of phosphorylation, however, was quite different between the two receptors when they were cross-linked by antigen. In membrane IgM-expressing cells, the substrate phosphorylation reached a maximum after 1 minute and diminished after 60 minutes whereas, in the membrane IgD-expressing cells, the substrate phosphorylation increased further over time, reached its maximum at 60 minutes, and persisted longer than 240 minutes after exposure to antigen. As a result, the intensity of protein tyrosine phosphorylation induced by cross-linking of membrane IgD was stronger than that induced by membrane IgM. Studies of chimeric receptors demonstrate that only the membrane-proximal C domain and/or the transmembrane part of membrane-bound IgD molecule is required for the long-lasting substrate phosphorylation. Together, these data suggest that the signal emission from the two receptors is controlled differently.


Tuberculosis in Liver Transplant Recipients: A Report of Eight Cases During a Five Year Period.
Tuberculosis incidence in Portugal ranged from 20 to 22 cases per 100 000 inhabitants between 2010 and 2014. Tuberculosis incidence in liver transplant recipients is not precisely known, but it is estimated to be higher than among the general population. Tuberculosis in liver transplant recipients is particularly challenging because of the atypical clinical presentation and side effects of the antibacillary drugs and their potential interactions with immunosuppressive therapies. We retrospectively reviewed the clinical records of liver transplant recipients with post-transplant tuberculosis occurring from January 2010 to December 2014 at a liver transplantation unit in Lisbon, Portugal. Demographic data, baseline and clinical features, as well as treatment regimen, toxicities and outcomes, were analyzed. Among 1005 recipients, active tuberculosis was diagnosed in eight patients between January 2010 and December 2014 (frequency = 0.8%). Late onset tuberculosis was more frequent than early tuberculosis. Mycobacterium tuberculosis complex was isolated from cultures in almost every case (7; 87.5%). Extra-pulmonary involvement and disseminated tuberculosis were frequent. Two patients developed rejection without allograft loss. Crude mortality was 37.5%, with 2 deaths being related to tuberculosis. Despite the uncertainty regarding treatment duration in liver transplant recipients, disease severity, as well as number of active drugs against TB infection, should be taken into account. There was a need for a rifampin-free regimen and immunosuppression adjustment in patients who experienced acute graf rejection. Although the number of cases of tuberculosis is low, its post-transplant frequency is significant and the observed mortality rate is not to be neglected. The cases of hepatotoxicity and graft rejection seen in this case series demonstrate the challenges associated with tuberculosis diagnosis in liver transplant recipients and management of the interactions between immunosuppressors and rifampin. This study strengthens the recommendation of latent tuberculosis infection screening and treatment in liver transplant candidates or recipients.


Defective gastrointestinal recovery after irradiation in W/Wv mice.
W/Wv mice are white, sterile, and have macrocytic anemia, all due to defective function of pertinent stem cell compartments. Sterility and coat color reflect stem cell failure during embryogenesis, while anemia results from a defective hematopoietic stem cell system which is active throughout life. Studies of radiation damage and recovery were undertaken to determine if the stem cell compartment of the intestinal mucosa, also active throughout life, is likewise affected. W/Wv mice "cured" of their hematopoietic defect, and normal littermates were exposed to 1,250 rads of whole-body irradiation. Mean survival time of controls was 8.4 plus or minus 0.31 days compared to only 5.85 plus or minus 0.18 days (P = LESS THAN0.001) FOR W/Wv. Incorporation of 3HTdR into mucosal cells of controls was minimum 2 days after exposure and exceeded nonirradiated levels by day 3, W/Wv values were lower than controls on days 2-4 and never significantly exceeded nonirradiated values. Changes in gut weight followed the same pattern. These studies suggest that the W/Wv defect involves stem cells of the gut and that the defect is a failure to proliferate and/or differentiate.


The eyes are sufficient to produce a threat superiority effect.
The research described in this article used a visual search task and demonstrated that the eye region alone can produce a threat superiority effect. Indeed, the magnitude of the threat superiority effect did not increase with whole-face, relative to eye-region-only, stimuli. The authors conclude that the configuration of the eyes provides a key signal of threat, which can mediate the search advantage for threat-related facial expressions.


Dynamical statistical shape priors for level set-based tracking.
In recent years, researchers have proposed introducing statistical shape knowledge into level set-based segmentation methods in order to cope with insufficient low-level information. While these priors were shown to drastically improve the segmentation of familiar objects, so far the focus has been on statistical shape priors which are static in time. Yet, in the context of tracking deformable objects, it is clear that certain silhouettes (such as those of a walking person) may become more or less likely over time. In this paper, we tackle the challenge of learning dynamical statistical models for implicitly represented shapes. We show how these can be integrated as dynamical shape priors in a Bayesian framework for level set-based image sequence segmentation. We assess the effect of such shape priors "with memory" on the tracking of familiar deformable objects in the presence of noise and occlusion. We show comparisons between dynamical and static shape priors, between models of pure deformation and joint models of deformation and transformation, and we quantitatively evaluate the segmentation accuracy as a function of the noise level and of the camera frame rate. Our experiments demonstrate that level set-based segmentation and tracking can be strongly improved by exploiting the temporal correlations among consecutive silhouettes which characterize deforming shapes.


Accuracy and reliability of remote retinopathy of prematurity diagnosis.
To determine the accuracy and reliability of retinopathy of prematurity (ROP) diagnosis using remote review of digital images by 3 masked ophthalmologist readers. An atlas was compiled of 410 retinal photographs from 163 eyes of 64 low-birth-weight infants taken using a wide-angle digital fundus camera. All the images were independently reviewed by 3 readers, and the diagnosis in each eye was classified into 1 of 4 ordinal categories: no ROP, mild ROP, type 2 prethreshold ROP, or ROP requiring treatment. Findings were compared with a reference standard of dilated indirect ophthalmoscopy with scleral depression performed by an experienced pediatric ophthalmologist. Sensitivities/specificities of the diagnosis of any ROP were 0.845/0.910 for the first reader, 0.816/0.955 for the second reader, and 0.864/0.493 for the third reader. Sensitivities/specificities of the diagnosis of ROP requiring treatment were 0.850/0.960 for the first reader, 0.850/0.973 for the second reader, and 0.900/0.953 for the third reader. When ROP was classified into ordinal categories, the overall weighted kappa for interreader reliability was 0.743. Intrareader reliability for detection of low-risk prethreshold ROP or worse was 100% for all readers. The accuracy, interreader reliability, and intrareader reliability of remote diagnosis of clinically relevant ROP based on digital imaging are substantial.


Serum pepsinogen I in relation to some clinical features and complications of duodenal ulcer disease.
Fasting serum pepsinogen 1 was assayed in 60 patients seen at the Kenyatta National Hospital with endoscopy - confirmed active duodenal ulceration. Pepsinogen 1 values were also correlated with some clinical features and complications of this disorder. 54 (90%) of the patients had significantly elevated values when compared with age and sex matched controls. Although elevated values were found in patients with chronic dyspepsia, family history of ulcer dyspepsia, history of gastro-duodenal blood loss and in patients with virulent ulcers, this did not show statistical significance. The possibility of using serum pepsinogen I to identify duodenal ulcer patients and to predict the clinical course and complications of this disorder is discussed.


fMRI activation in continuous and spike-triggered EEG-fMRI studies of epileptic spikes.
To evaluate functional magnetic resonance imaging (fMRI) with simultaneous EEG for finding metabolic sources of epileptic spikes. To find the localizing value of activated regions and factors influencing fMRI responses. Patients with focal epilepsy and frequent spikes were subjected to spike-triggered or continuous fMRI with simultaneous EEG. Results were analyzed in terms of fMRI activation, concordance with the location of EEG spiking and anatomic MRI abnormalities, and other EEG and clinical variables. In four patients, results also were compared with those of intracerebral EEG. Forty-eight studies were performed on 38 patients. Seventeen studies were not analyzed, primarily because no spikes occurred during scanning. Activation was obtained in 39% of 31 studies, with an activation volume of 2.55 +/- 4.84 cc. Activated regions were concordant with EEG localization in almost all studies and confirmed by intracerebral EEG in four patients. Forty percent of patients without an MRI lesion showed activation; 37.5% of patients with a lesion had an activation; the activation was near or inside the lesion. Bursts of spikes were more likely to generate an fMRI response than were isolated spikes (76 vs. 11%; p < 0.05). Combining EEG and fMRI in focal epilepsy yields regions of activation that are presumably the source of spiking activity. These regions are highly linked with epileptic foci and epileptogenic lesions in a significant number of patients. Activation also is found in patients with no visible MRI lesion. Intracerebral recordings largely confirm that these activation regions represent epileptogenic areas. It is still unclear why many patients show no activation.


A Comparative Study on the Life-Saving Radioprotective Effects of Vitamins A, E, C and Over-the-Counter Multivitamins.
Oral intake of vitamins which present antioxidant characteristics can protect living organisms against oxidative damage caused by exposure to ionizing radiation. It was previously reported that administration of high levels of vitamin C can lead to increased DNA damage through production of hydroxyl radicals from hydrogen peroxide by the Fenton reaction. However, our early experiments did not confirm this hypothesis. The main goal of this study was to determine if high doses of Vit C can show life-saving radioprotective effects. Phase I: Seventy two male Balb/c mice weighing 20-25g were randomly divided into six groups of 12 animals each. Group I; Vit E for five days, Groups II and III; Vit C and Vit A. Group 4; all three vitamins. Group V; an over-the-counter multivitamin. Group VI; none of the above. Phase II: 120 male BALB/c mice weighing 20-25g were randomly divided into 12 groups of 10 each. Group I; Vit A for five days. Groups II-IV; Vit C 200 mg/kg, 400 mg/kg, 800 mg/kg, respectively. Group V-VII; Vit E at daily doses of 200 iu/kg, 400 iu/kg, 800 iu/kg, respectively. Group VIII and IX; all three vitamins at low and high doses, respectively. Group X; an over-the-counter multivitamin. Group XI; controls group and Group XII; received pure olive oil. All animals (Phases I and II) were exposed to a lethal dose of gamma rays and the survival rates of the animals were monitored and recorded continuously for 16 days after exposure. Phase I: 14 days after irradiation the survival rate for control group was 33.33%, while the survival rates for the 1st to 5th groups were 45.45%, 81.81%, 50%, 57.14%, and 9.09% , respectively. Phase II: The survival rates in the control group and the group that only received pure olive oil, were 50% and 60%, respectively. Survival rate in the animals received Vit C at daily doses of 200 mg/kg, 400 mg/kg, 800 mg/kg, were 90%, 90% and 90%, respectively. Log rank (Mantel-Cox) test showed statistically significant differences between the survival rates in control irradiated mice (no vitamins) and mice received Vit C at daily doses of 200 mg/kg (P=0.042), 400 mg/kg (P=0.042) and 800 mg/kg (P=0.042). Altogether, findings of this study showed that even high doses of Vit C can show life-saving radioprotective effects. The significant radioprotective effect of Vit C at doses used in this study, opens new horizons in developing non-toxic, cost effective, easily available radioprotectors in life-threatening situations such as exposure to lethal doses of ionizing radiation. The radioprotective effect of Vit A and Vit E seem to be less efficient compared to that of Vit C.


Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease.
Parkinson disease is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic-ubiquitinated inclusions (Lewy bodies). Mutations in alpha-synuclein (A53T, A30P) and parkin cause familial Parkinson disease. Both these proteins are found in Lewy bodies. The absence of Lewy bodies in patients with parkin mutations suggests that parkin might be required for the formation of Lewy bodies. Here we show that parkin interacts with and ubiquitinates the alpha-synuclein-interacting protein, synphilin-1. Co-expression of alpha-synuclein, synphilin-1 and parkin result in the formation of Lewy-body-like ubiquitin-positive cytosolic inclusions. We further show that familial-linked mutations in parkin disrupt the ubiquitination of synphilin-1 and the formation of the ubiquitin-positive inclusions. These results provide a molecular basis for the ubiquitination of Lewy-body-associated proteins and link parkin and alpha-synuclein in a common pathogenic mechanism through their interaction with synphilin-1.


Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men.
Young adult males who cannot produce or respond to estrogen (E) are osteopenic, suggesting that E may regulate bone turnover in men, as well as in women. Both bioavailable E and testosterone (T) decrease substantially in aging men, but it is unclear which deficiency is the more important factor contributing to the increased bone resorption and impaired bone formation that leads to their bone loss. Thus, we addressed this issue directly by eliminating endogenous T and E production in 59 elderly men (mean age 68 years), studying them first under conditions of physiologic T and E replacement and then assessing the impact on bone turnover of withdrawing both T and E, withdrawing only T, or only E, or continuing both. Bone resorption markers increased significantly in the absence of both hormones and were unchanged in men receiving both hormones. By two-factor ANOVA, E played the major role in preventing the increase in the bone resorption markers, whereas T had no significant effect. By contrast, serum osteocalcin, a bone formation marker, decreased in the absence of both hormones, and both E and T maintained osteocalcin levels. We conclude that in aging men, E is the dominant sex steroid regulating bone resorption, whereas both E and T are important in maintaining bone formation.


Waldeyer's ring marginal zone B cell lymphoma: are the clinical and prognostic features nodal or extranodal? A study by the Consortium for Improving Survival of Lymphoma (CISL).
There has been controversy surrounding Waldeyer's ring (WR), especially focused on the question of whether it should be regarded as a nodal or an extranodal site. We conducted retrospective analyses of marginal zone B cell lymphomas involving WR (WR-MZLs) to observe their clinical features and prognosis, with specific regard to the nodal-or-extranodal question. A total of 52 patients with histological diagnosis of WR-MZL were retrospectively analyzed. The most common involvement site was the tonsil (40.4 %). Ann Arbor stage III/VI disease was present in 48.1 % (25 of 52). The response rate of the 27 stage I/II patients was 88.9 %, with 21 complete remissions and three partial remissions. The median time to progression (TTP) was 3.7 years (95 % CI 2.5-4.9 years). The estimated 5-year TTP and overall survival rates were 39.4 and 90.5 %, respectively. In a comparison with the historical data regarding extra-WR MALT lymphoma and nodal MZL (N-MZL), MALT lymphoma showed better TTP results than did WR-MZL and N-MZL (P < 0.001).


Metastatic Sertoli cell carcinoma of the testis.
Metastatic Sertoli cell tumor is a very rare and deadly disease accounting for approximately 1% of all testicular carcinomas. With fewer than 30 cases reported in the literature, there has not been a uniform treatment regimen with good results. Retroperitoneal lymph node dissection, chemotherapy, and radiation therapy in combination appear to offer the best outcome. This report describes the occurrence of this rare tumor in a 38-year-old man 2 years after left orchiectomy.


The long noncoding RNA Kcnq1ot1 organises a lineage-specific nuclear domain for epigenetic gene silencing.
Long noncoding RNAs are implicated in a number of regulatory functions in eukaryotic genomes. The paternally expressed long noncoding RNA (ncRNA) Kcnq1ot1 regulates epigenetic gene silencing in an imprinted gene cluster in cis over a distance of 400 kb in the mouse embryo, whereas the silenced region extends over 780 kb in the placenta. Gene silencing by the Kcnq1ot1 RNA involves repressive histone modifications, including H3K9me2 and H3K27me3, which are partly brought about by the G9a and Ezh2 histone methyltransferases. Here, we show that Kcnq1ot1 is transcribed by RNA polymerase II, is unspliced, is relatively stable and is localised in the nucleus. Analysis of conditional Dicer mutants reveals that the RNAi pathway is not involved in gene silencing in the Kcnq1ot1 cluster. Instead, using RNA/DNA FISH we show that the Kcnq1ot1 RNA establishes a nuclear domain within which the genes that are epigenetically inactivated in cis are frequently found, whereas nearby genes that are not regulated by Kcnq1ot1 are localised outside of the domain. The Kcnq1ot1 RNA domain is larger in the placenta than in the embryo, consistent with more genes in the cluster being silenced in the placenta. Our results show for the first time that autosomal long ncRNAs can establish nuclear domains, which might create a repressive environment for epigenetic silencing of adjacent genes. Long ncRNAs in imprinting clusters and the Xist RNA on the inactive X chromosome thus appear to regulate epigenetic gene silencing by similar mechanisms.


Potential use of high levels of vegetal proteins in diets for market-sized gilthead sea bream (Sparus aurata).
The effect of partial or total dietary substitution of fishmeal (FM) by vegetal protein sources on growth and feed efficiency was carried out in on-growing gilthead sea bream (mean initial weight 131 g). The Control diet (FM 100) contained FM as the primary protein source, while in Diets FM 25 and FM 0 the FM protein was replaced at 75% and 100%, respectively, by a vegetable protein mixture consisting of wheat gluten, soybean meal, rapeseed meal and crystalline amino acids. Diets FM 25 and FM 0 also contained krill meal at 47 g/kg in order to improve palatability. At the end of the trial (after 158 d), fish survival was above 90%. Final weight and the specific growth rate were statistically lower in fish fed the Control diet (361 g and 0.64%/d), compared with 390-396 g and 0.69-0.70%/d after feeding vegetal diets. No significant differences were found regarding feed intake and feed conversion ratio. The digestibility of protein and amino acids (determined with chromium oxide as indicator) was similar in all diets. The blood parameters were not significantly affected by treatments. The activity of trypsin and pepsin was significantly reduced after feeding Diet FM 0. In the distal intestine, the villi length in fish fed Diet FM 25 was significantly longer and the intestine of the fish fed the FM 100 diet showed a smaller number of goblet cells. In conclusion, a total FM substitution by a vegetal mix supplemented with synthetic amino acids in on-growing sea bream is feasible.


Sensing cisplatin-induced permeation of single live human bladder cancer cells by scanning electrochemical microscopy.
Cisplatin is a widely used anti-cancer agent, which was believed to trigger apoptosis of cancer cells by forming DNA adducts. However, recent studies evidenced a cisplatin-induced extrinsic apoptotic pathway through interaction with plasma membranes. We present quantitative time-course imaging of cisplatin-induced permeation of ferrocenemethanol to single live human bladder cancer cells (T24) using scanning electrochemical microscopy (SECM). Simultaneous quantification of cellular topography and membrane permeability was realized by running SECM in the depth scan mode. It was demonstrated that the acute addition of cisplatin to the outer environment of T24 cells immediately induced membrane permeability change in 5 min, which indicated a loosened structure of the cellular membrane upon cisplatin dosage. The cisplatin-induced permeation of T24 cells might be a one-step action, an extrinsic mechanism, since the cell response was quick, and no continuous increase in the membrane permeability was observed. The time-lapse SECM depth scan method provided a simple and facile way of monitoring cisplatin-induced membrane permeability changes. Our study is anticipated to lead to a methodology of screening anti-cancer drugs through their interactions with live cells.


Utility of CMR Markers of Myocardial Injury in Predicting LV Functional Recovery: Results from PROTECTION AMI CMR Sub-study.
Adverse left ventricular (LV) remodelling following acute ST-segment elevation myocardial infarction (STEMI) has prognostic importance. We aimed to predict 90-day left ventricular (LV) function following acute STEMI using variables from clinical presentation, biomarkers, and cardiovascular magnetic resonance imaging (CMR). Consecutive patients undergoing primary percutaneous coronary intervention for anterior STEMI as part of the Selective Inhibition of Delta-protein Kinase C for the Reduction of Infarct Size in Acute Myocardial Infarction (PROTECTION-AMI) trial were enrolled into the CMR sub-study at selected sites. CMR was performed at baseline (days 3 to 5) and 90 days and used to evaluate infarct size, myocardial salvage index, infarct heterogeneity, microvascular obstruction and global LV function. Biochemical markers including creatinine kinase area under the curve (CK AUC), peak CK, peak CK-myocardial band (CK-MB) and AUC, and troponin I were collected at specific time-points. Ninety-six patients were enrolled in the CMR sub study and 85 completed the 90-day follow-up, across 24 centres worldwide. LV ejection fraction (EF) was 56% (46-63%) at baseline and 60% (49-67%) at 90 days (p<0.001). Infarct size had moderate inverse correlation with 90-day EF (Spearman's rho=-0.7, p < 0.001) and had the strongest correlation when compared to myocardial salvage index (Spearman's rho=0.5, p=0.001), infarct heterogeneity (Spearman's rho=-0.4, p=0.02 or microvascular obstruction (Spearman's rho=-0.4, p<0.001). All biochemical markers had similar moderate relationship to LVEF at 90 days (Spearman's rho -0.6 to -0.8, p=0.001). In a multivariable model, only baseline LVEF, CMR infarct size and infarct heterogeneity independently predicted 90-day LVEF. This study reports findings of a combined CMR protocol (including myocardial oedema imaging) in a multi-centre, multi-vendor setting. We found infarct size, infarct heterogeneity and myocardial salvage index correlated favourably with 90-day LVEF, however only the former two were independently predictive.


Proteoglycans of human rotator cuff tendons.
Rotator cuff and biceps tendons that appeared grossly normal were procured from adult cadavers without a history of shoulder problems. These tendons were analyzed for the amount and type of glycosaminoglycan, type of proteoglycan, and histology. When compared with the distal/tensional region of biceps tendon, the glycosaminoglycan content of supraspinatus, infraspinatus, and subscapularis tendons was 2.5-fold higher and the glycosaminoglycan content of the proximal/compressed region of biceps tendon was 3-fold higher. The ratio of hyaluronic acid to chondroitin sulfate/dermatan sulfate in all three cuff tendons was approximately 1. Rotator cuff tendons contained large proteoglycan similar to aggrecan, as demonstrated by sodium dodecyl sulfate-polyacrylamide gel migration elution from Sepharose CL-4B, and content of both chondroitin sulfate and keratan sulfate chains. Both decorin and biglycan were also present, as demonstrated by migration in sodium dodecyl sulfate-polyacrylamide gels and core protein immunoreactivity. In contrast decorin was the only proteoglycan prominent in distal/tensional regions of biceps tendon. Histological analysis showed layers of loosely organized alcian blue-stained material running between the longitudinal collagen fiber bundles. The proteoglycan content of rotator cuff tendons was similar to fibrocartilage in tendons that have been subjected to compressive loads in situ. This suggests that cells of normal adult rotator cuff tendons have adapted to loads distinct from pure tension. However, the histological organization did not resemble mature fibrocartilage. The increased amount of proteoglycan in rotator cuff tendons may serve to separate and lubricate collagen bundles as they move relative to each other during normal shoulder motion.


North Wales randomized controlled trial of cognitive behaviour therapy for acute schizophrenia spectrum disorders: two-year follow-up and economic evaluation.
There is good evidence now that cognitive behaviour therapy (CBT) is effective in the treatment of people suffering from schizophrenia. There is also some evidence that the benefits of CBT persist after the end of treatment and that the direct costs of providing CBT as an adjunct to standard care are no higher than the direct costs of standard care alone. The aims of the present study were to discover if the benefits of CBT for acute schizophrenia which were found 1 year after index admission persist for another year, and to evaluate the comparative costs of providing CBT. Consecutive admissions meeting criteria were recruited. After screening, 43 were assigned at random to a treatment-as-usual (TAU) control group and 47 were assigned to TAU plus CBT. Patients (73% of original) were rated on symptoms and social functioning 2 years after index admission. An evaluation of the direct costs of services was also completed. The CBT group had maintained its advantage over the TAU group on negative symptoms and social functioning but had lost the advantage it previously enjoyed in positive symptoms. The difference between groups in total direct costs over the 2 years was not statistically significant despite the cost of providing CBT. Some of the benefits of CBT for patients suffering acute psychotic episodes persist for 2 years. After the end of regular treatment, CBT should probably be targeted on the appearance of early signs of relapse to forestall the re-emergence of positive symptoms.


A Global Analysis of CYP51 Diversity and Azole Sensitivity in Rhynchosporium commune.
CYP51 encodes the target site of the azole class of fungicides widely used in plant protection. Some ascomycete pathogens carry two CYP51 paralogs called CYP51A and CYP51B. A recent analysis of CYP51 sequences in 14 European isolates of the barley scald pathogen Rhynchosporium commune revealed three CYP51 paralogs, CYP51A, CYP51B, and a pseudogene called CYP51A-p. The same analysis showed that CYP51A exhibits a presence/absence polymorphism, with lower sensitivity to azole fungicides associated with the presence of a functional CYP51A. We analyzed a global collection of nearly 400 R. commune isolates to determine if these findings could be extended beyond Europe. Our results strongly support the hypothesis that CYP51A played a key role in the emergence of azole resistance globally and provide new evidence that the CYP51A gene in R. commune has further evolved, presumably in response to azole exposure. We also present evidence for recent long-distance movement of evolved CYP51A alleles, highlighting the risk associated with movement of fungicide resistance alleles among international trading partners.


Preventive Effects of Houttuynia cordata Extract for Oral Infectious Diseases.
Houttuynia cordata (HC) (Saururaceae) has been used internally and externally as a traditional medicine and as an herbal tea for healthcare in Japan. Our recent survey showed that HC poultice (HCP) prepared from smothering fresh leaves of HC had been frequently used for the treatment of purulent skin diseases with high effectiveness. Our experimental study also demonstrated that ethanol extract of HCP (eHCP) has antibacterial, antibiofilm, and anti-inflammatory effects against S. aureus which caused purulent skin diseases. In this study, we focused on novel effects of HCP against oral infectious diseases, such as periodontal disease and dental caries. We determined the antimicrobial and antibiofilm effects of water solution of HCP ethanol extract (wHCP) against important oral pathogens and investigated its cytotoxicity and anti-inflammatory effects on human oral epithelial cells. wHCP had moderate antimicrobial effects against some oral microorganisms and profound antibiofilm effects against Fusobacterium nucleatum, Streptococcus mutans, and Candida albicans. In addition, wHCP had no cytotoxic effects and could inhibit interleukin-8 and CCL20 productions by Porphyromonas gingivalis lipopolysaccharide-stimulated human oral keratinocytes. Our findings suggested that wHCP may be clinically useful for preventing oral infectious diseases as a mouthwash for oral care.


Factors Associated with Recurrence and Regional Adenopathy for Head and Neck Cutaneous Squamous Cell Carcinoma.
Objective Cutaneous squamous cell carcinoma (CSCC) is one of the most common malignancies worldwide. With advanced CSCC of the head and neck, there is conflicting evidence on what constitutes high-risk disease. Our objective is to evaluate which factors are predictive of recurrence and nodal spread and survival. Study Design Case series with chart review. Setting Tertiary academic institution. Subjects and Methods Patients with advanced head and neck CSCC treated with primary resection identified by chart review. Results A total of 212 patients met inclusion criteria, with a mean age of 70.4 years; 87.3% were men. Mean tumor diameter was 3.65 cm, with an average depth of invasion of 1.38 cm. The mean follow-up time was 35 months (median, 21.5), and over that period 67 recurrences were recorded, 49 of which were local. The 5-year Kaplan-Meier estimate of disease-free survival for the cohort was 53.2%. On Cox multivariate analysis, recurrent disease, perineural invasion (PNI), and poorly differentiated histology were independent predictors of recurrence. On multinomial logistic regression, patients with primary tumors on the ear, cheek, temple, or lip, as well as those with PNI, were more likely to present with nodal metastasis. Conclusion For advanced CSCCs of the head and neck, patients with recurrent disease, PNI, and poorly differentiated tumors are at highest risk for local recurrence. Patients with tumors or the ear, cheek, temple, or lip, as well as those with PNI, are at increased risk of harboring nodal disease.


Evaluation of inhaler techniques among asthma patients seen in Nigeria: an observational cross sectional study.
An Adequate and an effective dose of inhalation drugs can be administered only if the correct inhaler-specific technique is followed by asthma patients. There is paucity of data on this subject among Nigerians and Africans. This observational study was to assess the inhaler techniques among asthma patients in Nigeria and also to identify the factors related to an inaccurate or poor inhaler use. Consenting asthma patients on inhalers, who attended medical out-patients clinic, of two university hospitals in Nigeria were asked to use their inhalers while an inhaler-administration checklist was used to assess each patients inhaler technique. Information on demographics, asthma symptoms history and history of technique education were obtained. Data was analyzed using standard statistical methods. A total of 140 asthma patients participated out of which 75 were females. All the patients used pressurized metered dose inhalers (pMDI) type; 51 of them used dry powder inhalers (DPI) in addition. For pMDI, 22.1% (31/140) completed all required steps while 37.3% (19/51) did so for DPI (P = 0.04). Patients with higher educational qualification (P < 0.01) and those with less frequent asthma symptoms (P < 0.01) are more likely to use the pMDI inhalers more accurately while patients who have been taught previously by a Doctor were more likely to use the DPI better. Majority of asthma patients use their inhalers inaccurately. Patient-dependent factors were identified as the cause of incorrect technique of inhaler use. Asthma patients on inhalation medications should have routine assessment of their inhaler technique at every visit and corrected if found to be poor.


Degradation in carbon stocks near tropical forest edges.
Carbon stock estimates based on land cover type are critical for informing climate change assessment and landscape management, but field and theoretical evidence indicates that forest fragmentation reduces the amount of carbon stored at forest edges. Here, using remotely sensed pantropical biomass and land cover data sets, we estimate that biomass within the first 500 m of the forest edge is on average 25% lower than in forest interiors and that reductions of 10% extend to 1.5 km from the forest edge. These findings suggest that IPCC Tier 1 methods overestimate carbon stocks in tropical forests by nearly 10%. Proper accounting for degradation at forest edges will inform better landscape and forest management and policies, as well as the assessment of carbon stocks at landscape and national levels.


Neuroplasticity of language in left-hemisphere stroke: Evidence linking subsecond electrophysiology and structural connections.
The understanding of neuroplasticity following stroke is predominantly based on neuroimaging measures that cannot address the subsecond neurodynamics of impaired language processing. We combined behavioral and electrophysiological measures and structural-connectivity estimates to characterize neuroplasticity underlying successful compensation of language abilities after left-hemispheric stroke. We recorded the electroencephalogram from patients with stroke lesions to the left temporal lobe and from matched controls during context-driven word retrieval. Participants heard lead-in sentences that either constrained the final word ("He locked the door with the") or not ("She walked in here with the"). The last word was shown as a picture to be named. Individual-participant analyses were conducted, focusing on oscillatory power as a subsecond indicator of a brain region's functional neurophysiological computations. All participants named pictures faster following constrained than unconstrained sentences, except for two patients, who had extensive damage to the left temporal lobe. Left-lateralized alpha-beta oscillatory power decreased in controls pre-picture presentation for constrained relative to unconstrained contexts. In patients, the alpha-beta power decreases were observed with the same time course as in controls but were lateralized to the intact right hemisphere. The right lateralization depended on the probability of white-matter connections between the bilateral temporal lobes. The two patients who performed poorly behaviorally showed no alpha-beta power decreases. Our findings suggest that incorporating direct measures of neural activity into investigations of neuroplasticity can provide important neural markers to help predict language recovery, assess the progress of neurorehabilitation, and delineate targets for therapeutic neuromodulation. Hum Brain Mapp 38:3151-3162, 2017. © 2017 Wiley Periodicals, Inc.


Effects of maternal care on the lifetime reproductive success of females in a neotropical harvestman.
1. Few studies have experimentally quantified the costs and benefits of female egg-guarding behaviour in arthropods under field conditions. Moreover, there is also a lack of studies assessing separately the survival and fecundity costs associated with this behavioural trait. 2. Here we employ field experimental manipulations and capture-mark-recapture methods to identify and quantify the costs and benefits of egg-guarding behaviour for females of the harvestman Acutisoma proximum Mello-Leitão, a maternal species from south-eastern Brazil. 3. In a female removal experiment that lasted 14 days, eggs left unattended under natural conditions survived 75.6% less than guarded eggs, revealing the importance of female presence preventing egg predation. 4. By monitoring females' reproductive success for 2 years, we show that females experimentally prevented from guarding their eggs produced new clutches more frequently and had mean lifetime fecundity 18% higher than that of control guarding females. 5. Regarding survival, our capture-mark-recapture study does not show any difference between the survival rates of females prevented from caring and that of control guarding females. 6. We found that experimentally females prevented from guarding their eggs have a greater probability to produce another clutch (0.41) than females that cared for the offspring (0.34), regardless of their probability of surviving long enough to do that. 7. Our approach isolates the ecological costs of egg-guarding that would affect survival, such as increased risk of predation, and suggests that maternal egg-guarding also constrains fecundity through physiological costs of egg production. 8. Weighting costs and benefits of egg-guarding we demonstrate that the female's decision to desert would imply an average reduction of 73.3% in their lifetime fitness. Despite the verified fecundity costs of egg-guarding, this behaviour increases female fitness due to the crucial importance of female presence aimed to prevent egg predation.


Multiaperture imaging.
We study the reconstruction of a high-resolution image from multiple low-resolution images by using a nonlinear iterative backprojection algorithm. We exploit diversities in the imaging channels, namely, the number of imagers, magnification, position, rotation, and fill factor, to undo the degradation caused by the optical blur, pixel blur, and additive noise. We quantify the improvements gained by these diversities in the reconstruction process and discuss the trade-off among system parameters. As an example, for a system in which the pixel size is matched to the diffraction-limited optical blur size at a moderate detector noise level, we can reduce the reconstruction root-mean-square error by 570% by using 16 cameras and a large amount of diversity. The algorithm was implemented on a 56 camera array specifically constructed to demonstrate the resolution-enhancement capabilities. Practical issues associated with building and operating this device are presented and analyzed.


Detection of flap venous and arterial occlusion using interstitial glucose monitoring in a rodent model.
Free tissue transfer necessitates vigilant postoperative monitoring for vessel occlusion. Unfortunately, most monitoring methods require experienced personnel and are expensive to use. Furthermore, many tests have low sensitivity, low specificity, or significant delay between vessel occlusion and detection. The authors report on a novel method of tissue monitoring that avoids these limitations by tracking interstitial glucose concentration. Vertical rectus abdominis myocutaneous flaps were elevated in adult rats based on the superior epigastric vessels. Interstitial glucose within the flaps was monitored using a transcutaneous sensor. Interstitial glucose was recorded following arterial occlusion in 10 flaps and venous occlusion was recorded in eight flaps. Criteria for detecting vessel occlusion were developed based on interstitial glucose concentration and rate of change. Occlusion of the flap's arterial supply led to a rapid decline in interstitial glucose. Within 15 minutes of arterial occlusion, the interstitial glucose in occluded flaps was significantly lower than in viable flaps (p = 0.0003). Occlusion of venous outflow resulted in a similar decline of interstitial glucose. Interstitial glucose below the animal's euglycemic range was 100 percent sensitive (95 percent confidence interval, 78.1 to 100 percent) and 95.2 percent specific (95 percent confidence interval, 74.1 to 99.8 percent) for vessel occlusion. A fall in interstitial glucose greater than or equal to 7 mg/dl per minute was 100 percent sensitive (95 percent confidence interval, 78.1 to 100 percent) and 100 percent specific (95 percent confidence interval, 80.8 to 100 percent) for vessel occlusion. The delay between occlusion and detection was less than 30 minutes for all flaps. Interstitial glucose monitoring is highly sensitive and specific for vessel occlusion. This technology offers a rapid, inexpensive, and accurate method of monitoring free tissue transfers.


Timing of milestone competency acquisition in neurology residency: What by when?
To determine the stage of training at which neurology residents should achieve individual elements of the Accreditation Council for Graduate Medical Education neurology Milestones and to examine the relationship between perceived importance of Milestones and the stage by which they should be achieved. A modified Delphi technique was used to establish consensus postgraduate year (PGY) expectations for neurology Milestone competencies across 3 geographically and administratively distinct Mayo Clinic neurology residency programs. Timing expectations were examined for relationships to perceived importance of the individual Milestones and effects of participant characteristics. PGY expectations for neurology Milestone elements ranged from PGY 1.3 to PGY 4.1. Extent of rater educational seniority had no effect on PGY competency expectations. There was a moderate inverse relationship between perceived importance of the Milestone element and the PGY by which it should be achieved (r s = -0.74, p < 0.0001). Expectations for neurology Milestone competency acquisition can be measured and may help inform individual program design, educational expectations, and future Milestone design.


Too hot to handle: Unprecedented seagrass death driven by marine heatwave in a World Heritage Area.
The increased occurrence of extreme climate events, such as marine heatwaves (MHWs), has resulted in substantial ecological impacts worldwide. To date, metrics of thermal stress within marine systems have focussed on coral communities, and less is known about measuring stress relevant to other primary producers, such as seagrasses. An extreme MHW occurred across the Western Australian coastline in the austral summer of 2010-2011, exposing marine communities to summer seawater temperatures 2-5°C warmer than average. Using a combination of satellite imagery and in situ assessments, we provide detailed maps of seagrass coverage across the entire Shark Bay World Heritage Area (ca. 13,000 km2 ) before (2002 and 2010) and after the MHW (2014 and 2016). Our temporal analysis of these maps documents the single largest loss in dense seagrass extent globally (1,310 km2 ) following an acute disturbance. Total change in seagrass extent was spatially heterogeneous, with the most extensive declines occurring in the Western Gulf, Wooramel Bank and Faure Sill. Spatial variation in seagrass loss was best explained by a model that included an interaction between two heat stress metrics, the most substantial loss occurring when degree heating weeks (DHWm) was ≥10 and the number of days exposed to extreme sea surface temperature during the MHW (DaysOver) was ≥94. Ground truthing at 622 points indicated that change in seagrass cover was predominantly due to loss of Amphibolis antarctica rather than Posidonia australis, the other prominent seagrass at Shark Bay. As seawater temperatures continue to rise and the incidence of MHWs increase globally, this work will provide a basis for identifying areas of meadow degradation, or stability and recovery, and potential areas of resilience.


Accuracy of MUAC in the detection of severe wasting with the new WHO growth standards.
The objectives of this study were to estimate the accuracy of using mid-upper-arm circumference (MUAC) measurements to diagnose severe wasting by comparing the new standards from the World Health Organization (WHO) with those from the US National Center for Health Statistics (NCHS) and to analyze the age independence of the MUAC cutoff values for both curves. We used cross-sectional anthropometric data for 34,937 children between the ages of 6 and 59 months, from 39 nutritional surveys conducted by Doctors Without Borders. Receiver operating characteristic curves were used to examine the accuracy of MUAC diagnoses. MUAC age independence was analyzed with logistic regression models. With the new WHO curve, the performance of MUAC measurements, in terms of sensitivity and specificity, deteriorated. With different cutoff values, however, the WHO standards significantly improved the predictive value of MUAC measurements over the NCHS standards. The sensitivity and specificity of MUAC measurements were the most age independent when the WHO curve, rather than the NCHS curve, was used. This study confirms the need to change the MUAC cutoff value from <110 mm to <115 mm. This increase of 5 mm produces a large change in sensitivity (from 16% to 25%) with little loss in specificity, improves the probability of diagnosing severe wasting, and reduces false-negative results by 12%. This change is needed to maintain the same diagnostic accuracy as the old curve and to identify the children at greatest risk of death resulting from severe wasting.


Predictors of Nondiagnostic Ultrasound for Appendicitis.
Ionizing radiation and cost make ultrasound (US), when available, the first imaging study for the diagnosis of suspected pediatric appendicitis. US is less sensitive and specific than computed tomography (CT) or magnetic resonance imaging (MRI) scans, which are often performed after nondiagnostic US. We sought to determine predictors of nondiagnostic US in order to guide efficient ordering of imaging studies. A prospective cohort study of consecutive patients 4 to 30 years of age with suspected appendicitis took place at an emergency department with access to 24/7 US, MRI, and CT capabilities. Patients with US as their initial study were identified. Clinical (i.e., duration of illness, highest fever, and right lower quadrant pain) and demographic (i.e., age and sex) variables were collected. Body mass index (BMI) was calculated based on Centers for Disease Control and Prevention criteria; BMI >85th percentile was categorized as overweight. Patients were followed until day 7. Univariate and stepwise multivariate logistic regression analysis was performed. Over 3 months, 106 patients had US first for suspected appendicitis; 52 (49%) had nondiagnostic US results. Eighteen patients had appendicitis, and there were no missed cases after discharge. On univariate analysis, male sex, a yearly increase in age, and overweight BMI were associated with nondiagnostic US (p < 0.05). In the multivariate model, only BMI (odds ratio 4.9 [95% CI 2.0-12.2]) and age (odds ratio 1.1 [95% CI 1.02-1.20]) were predictors. Sixty-eight percent of nondiagnostic US results occurred in overweight patients. Overweight and older patients are more likely to have a nondiagnostic US or appendicitis, and it may be more efficient to consider alternatives to US first for these patients. Also, this information about the accuracy of US to diagnose suspected appendicitis may be useful to clinicians who wish to engage in shared decision-making with the parents or guardians of children regarding imaging options for children with acute abdominal pain.


Enhanced expression of selenocysteine lyase in acute glomerulonephritis and its regulation by AP-1.
Acute glomerulonephritis can lead to chronic glomerulonephritis or resolve without permanent damage to the kidneys. Differential gene expression was studied in a model of acute and chronic glomerulonephritis to identify factors influencing the course of glomerulonephritis towards healing or chronification. One of the differentially expressed genes was identified as SCL, encoding selenocysteine lyase. Its expression was higher in acute glomerulonephritis and lower in chronic glomerulonephritis. The transcriptional regulation of SCL was studied in vitro in rat mesangial cells (MC). SCL RNA expression increased eight-fold compared to the baseline after stimulation with interleukin-1beta (IL-1beta) for three hours. Luciferase expression and gel shift experiments revealed an enhancer element between bp -152 and -298 of the SCL 5'-regulatory region, with protein binding to an AP-1 binding site that may be involved in the regulation of SCL-RNA in vivo in an endogenous feedback mechanism to the inflammatory reaction in acute glomerulonephritis, leading to resolution of this disease.


Novel immunotherapy vaccine development.
Allergen-specific immunotherapy is the only curative treatment for allergic diseases. In spite of the great progress in both vaccine development and the methods of allergen immunotherapy (AIT) in recent years, several key problems related to limited efficacy, side-effects, low patient adherence and the relatively high costs due to the long duration (3-5 years) remain to be solved. The current approaches aiming at optimization of AIT are reviewed, including both conceptual studies in experimental models and proof-of-concept - as well as large, multicenter clinical studies. The most promising approaches to improve efficacy and safety of vaccine-based AIT include bypassing IgE binding and targeting allergen-specific T cells using hypoallergenic recombinant allergen derivatives and immunogenic peptides, the use of new adjuvants and stimulators of the innate immune response, the fusion of allergens to immune modifiers and peptide carrier proteins and new routes of vaccine administration. The cloning of allergen proteins and genetic engineering enabled the production of vaccines that have well defined molecular, immunologic and biologic characteristics as well as modified molecular structure. These new compounds along with new immunization protocols can bring us closer to the ultimate goal of AIT, that is, complete cure of a large number of allergic patients.


Association analysis of the COMT/MTHFR genes and geriatric depression: an MRI study of the putamen.
Catechol-O-Methyltransferase (COMT) and Methylenetetrahydrofolate reductase (MTHFR) had been reported to relate to depression but with inconsistent results. The basal ganglia are also important in the pathophysiology of affective disorder via connections with limbic system and prefrontal cortex. The authors examined the relationship between an interaction of COMT/MTHFR polymorphisms and volumes of putamen in depressed and nondepressed elders. Participants included 170 depressed and 83 nondepressed subjects aged 60 years or older. Subjects completed cross-sectional assessments, including clinical evaluation, brain magnetic resonance imaging (MRI) scan, and COMT Val158Met and MTHFR C677T genotyping. Putamen volumes were measured using 1.5-Tesla whole-body MRI system. Statistical models examined the relationship between COMT/MTHFR genotype, proportional volumes of putamen and depression while controlling for age and sex. After controlling for covariates, among depressed subjects with MTHFR C/C, both the right and left putamen had smaller volumes as the number of COMT 158Val increased. The left putamen volumes of depressed subjects with COMT Met/Met were smaller as the number of MTHFR 677T increased compared to nondepressed subjects. Our findings do not support a major role for COMT or MTHFR alone. However, an epigenetic interaction of COMT Val158Met and MTHFR C677T polymorphisms may contribute to putamen volumes differences between depressed and nondepressed subjects. Further studies with a larger sample size are necessary to support a genetically based role for basal ganglia structures in the etiopathogenesis of depression.


Late-onset Crohn's disease: a comparison of disease behaviour and therapy with younger adult patients: the Italian Group for the Study of Inflammatory Bowel Disease 'AGED' study.
Disease phenotype and outcome of late-onset Crohn's disease are still poorly defined. In this Italian nationwide multicentre retrospective study, patients diagnosed ≥65 years (late-onset) were compared with young adult-onset with 16-39 years and adult-onset Crohn's disease 40-64 years. Data were collected for 3 years following diagnosis. A total of 631 patients (late-onset 153, adult-onset 161, young adult-onset 317) were included. Colonic disease was more frequent in late-onset (P < 0005), stenosing behaviour was more frequent than in adult-onset (P < 0003), but fistulising disease was uncommon. Surgery rates were not different between the three age groups. Systemic steroids were prescribed more frequently in young adult-onset in the first year, but low bioavailability steroids were used more frequently in late-onset in the first 2 years after diagnosis (P < 0.036, P < 0.041, respectively). The use of immunomodulators and anti-TNF's even in patients with more complicated disease, that is, B2 or B3 behaviour (Montreal classification), remained significantly inferior (P < 0.0001) in late-onset compared to young adult-onset. Age at diagnosis, Charlson comorbidity index, and steroid used in the first year were negatively associated with the use of immunomodulators and biologics. Comorbidities, related medications and hospitalizations were more frequent in late-onset. Polypharmacy was present in 56% of elderly Crohn's disease patients. Thirty-two percent of late-onset Crohn's disease presented with complicated disease behaviour. Despite a comparable use of steroids and surgery, immunomodulators and biologics were used in a small number of patients.


Scaling hetero-epitaxy from layers to three-dimensional crystals.
Quantum structures made from epitaxial semiconductor layers have revolutionized our understanding of low-dimensional systems and are used for ultrafast transistors, semiconductor lasers, and detectors. Strain induced by different lattice parameters and thermal properties offers additional degrees of freedom for tailoring materials, but often at the expense of dislocation generation, wafer bowing, and cracks. We eliminated these drawbacks by fast, low-temperature epitaxial growth of Ge and SiGe crystals onto micrometer-scale tall pillars etched into Si(001) substrates. Faceted crystals were shown to be strain- and defect-free by x-ray diffraction, electron microscopy, and defect etching. They formed space-filling arrays up to tens of micrometers in height by a mechanism of self-limited lateral growth. The mechanism is explained by reduced surface diffusion and flux shielding by nearest-neighbor crystals.


The preoperative hemoglobin, albumin, lymphocyte and platelet (HALP) score is a useful predictor in patients with resectable esophageal squamous cell carcinoma.
The hemoglobin, albumin, lymphocyte and platelet (HALP) score has been confirmed as a prognostic factor in several types of cancers. The current study aimed to assess the prognostic value of preoperative HALP score, an inflammatory and nutritional based score, in predicting cancer-specific survival (CSS) in resectable patients undergoing curative resection for esophageal squamous cell carcinoma (ESCC). The clinical data of 355 consecutive patients with ESCC who underwent curative resection were retrospectively conducted and analyzed. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value for preoperative HALP. The areas under the curve (AUC) for preoperative HALP and other variables were calculated and compared. Cox regression analyses and Kaplan-Meier methods were used to identify the factors associated with CSS. According to the ROC curve, the optimal cut-off value for preoperative HALP was 31.8. The 5-year CSS for preoperative HALP low (≤31.8) and high (>31.8) was 15.1% and 47.5%, respectively (p < 0.001). Preoperative HALP had reliable abilities to predict CSS in resectable ESCC patients in any stage or gender, according to the subgroup analysis based on the patients' cancer stage and gender. Multivariate analyses confirmed that preoperative HALP was an independent prognostic score regarding CSS in patients with resectable ESCC (p < 0.001). This study confirmed that the postoperative HALP score could be regarded as a potential independent prognostic factor for CSS in patients with resectable ESCC.


Mass sperm motility is associated with fertility in sheep.
The study was to focus on the relationship between wave motion (mass sperm motility, measured by a mass sperm motility score, manually assessed by artificial insemination (AI) center operators) and fertility in male sheep. A dataset of 711,562 artificial inseminations performed in seven breeds by five French AI centers during the 2001-2005 time period was used for the analysis. Factors influencing the outcome of the insemination, which is a binary response observed at lambing of either success (1) or failure (0), were studied using a joint model within each breed and AI center (eight separate analyses). The joint model is a multivariate model where all information related to the female, the male and the insemination process were included to improve the estimation of the factor effects. Results were consistent for all analyses. The male factors affecting AI results were the age of the ram and the mass motility. After correction for the other factors of variation, the lambing rate increased quasi linearly from three to more than ten points with the mass sperm motility score depending on the breed and the AI center. The consistency of the relationship for all breeds indicated that mass sperm motility is predictive of the fertility resulting when sperm are used from a specific ejaculate. Nonetheless, predictability could be improved if an objective measurement of mass sperm motility were available as a substitute for the subjective scoring currently in use in AI centers.


Jews and their intraethnic vulnerability to affective disorders, fact or artifact? II: Evidence from a cohort study.
This paper, which complements a prior review of published studies, reports findings from a community-based survey of 4,914 Israel-born offspring of immigrants from Europe (Ashkenazim) and North Africa. Respondents were examined by psychiatrists using the Schedule for Affective Disorders and Schizophrenia, Israel version, and diagnosed with the Research Diagnostic Criteria. Unlike previous studies, this investigation found that Israelis of North African origin had significantly higher rates of affective disorders, including major depressive and intermittent depressive disorders. The Ashkenazim, however, had higher rates of bipolar I disorder at the definite level of diagnosis. Differential patterns in help-seeking may account for the divergent findings between this community-based study and earlier treatment-based reports. These results suggest the need to further investigate social and genetic etiological factors that may explain the differential rates.


Antibody recognition of heterologous variant surface antigens after a single Plasmodium falciparum infection in previously naive adults.
Antibodies to variant surface antigens (VSA) including Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) have been associated with protective antimalarial immunity that appears to be variant-specific. This study of adult returned travelers with a single acute P. falciparum infection investigated whether a primary antibody response includes IgG specific for heterologous VSA. We found that 11 of 14 patients had IgG reactive with up to six P. falciparum lines expressing different heterologous PfEMP1 variants, measured by flow cytometry (reactivity greater than two times the mean of the negative control sera was defined as "positive"), with high reactivity (greater than four times the mean of the negative controls) detected in three patients. The dominant variant(s) recognized differed between seropositive individuals. Despite previous evidence that antibody responses to heterologous VSA are short-lived, seven patients had detectable IgG at > 20 weeks post-infection. Together these data suggest that a single P. falciparum infection can be sufficient to induce antibodies reactive with several PfEMP1 variants, although the repertoire of target epitopes they recognize may still be restricted.


Identification and biochemical characterization of novel putative substrates for the epidermal growth factor receptor kinase.
To gain insight into the mechanisms which control the mitogenic response to epidermal growth factor (EGF), we have partially purified and characterized several intracellular proteins which are phosphorylated on tyrosine residues following activation of the epidermal growth factor receptor (EGFR). Partial purification was achieved by immunoaffinity chromatography using immobilized anti-phosphotyrosine antibodies. Antisera generated against the partially purified proteins were used to identify at least five novel EGFR putative substrates, designated, on the basis of their apparent molecular weight, p97, p68, p61, p56, and p23. All of these proteins became specifically phosphorylated on tyrosine after EGF treatment of intact cells, as assessed by phosphoamino acid analysis, and none of them represented an EGFR degradation product. The phosphorylation of these proteins appeared to be relatively specific for the EGFR. In particular, an EGFR-related kinase, erbB-2 was much less efficient than EGFR at phosphorylating p97, p56, and p23 and incapable of phosphorylating p68. The identification of these novel EGFR putative substrates should lead to a better understanding of the mechanisms controlling the specificity of EGFR-mediated mitogenic signaling.


Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction.
To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction. Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs. Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy.


Diagnostic and prognostic value of plasma neurofilament light and total-tau in sporadic Creutzfeldt-Jakob disease.
Blood neurofilament light (Nfl) and total-tau (t-tau) have been described to be increased in several neurological conditions, including prion diseases and other neurodegenerative dementias. Here, we aim to determine the accuracy of plasma Nfl and t-tau in the differential diagnosis of neurodegenerative dementias and their potential value as prognostic markers of disease severity. Plasma Nfl and t-tau were measured in healthy controls (HC, n = 70), non-neurodegenerative neurological disease with (NND-Dem, n = 17) and without dementia syndrome (NND, n = 26), Alzheimer's disease (AD, n = 44), Creutzfeldt-Jakob disease (CJD, n = 83), dementia with Lewy bodies/Parkinson's disease with dementia (DLB/PDD, n = 35), frontotemporal dementia (FTD, n = 12), and vascular dementia (VaD, n = 22). Biomarker diagnostic accuracies and cutoff points for the diagnosis of CJD were calculated, and associations between Nfl and t-tau concentrations with other fluid biomarkers, demographic, genetic, and clinical data in CJD cases were assessed. Additionally, the value of Nfl and t-tau predicting disease survival in CJD was evaluated. Among diagnostic groups, highest plasma Nfl and t-tau concentrations were detected in CJD (fold changes of 38 and 18, respectively, compared to HC). Elevated t-tau was able to differentiate CJD from all other groups, whereas elevated Nfl concentrations were also detected in NND-Dem, AD, DLB/PDD, FTD, and VaD compared to HC. Both biomarkers discriminated CJD from non-CJD dementias with an AUC of 0.93. In CJD, plasma t-tau, but not Nfl, was associated with PRNP codon 129 genotype and CJD subtype. Positive correlations were observed between plasma Nfl and t-tau concentrations, as well as between plasma and CSF concentrations of both biomarkers (p < 0.001). Nfl was increased in rapidly progressive AD (rpAD) compared to slow progressive AD (spAD) and associated to Mini-Mental State Examination results. However, Nfl displayed higher accuracy than t-tau discriminating CJD from rpAD and spAD. Finally, plasma t-tau, but not plasma Nfl, was significantly associated with disease duration, offering a moderate survival prediction capacity. Plasma Nfl and t-tau are useful complementary biomarkers for the differential diagnosis of CJD. Additionally, plasma t-tau emerges as a potential prognostic marker of disease duration.


The lifetime cost of diabetes and its implications for diabetes prevention.
To assess the cost implications of diabetes prevention, it is important to know the lifetime medical cost of people with diabetes relative to those without. We derived such estimates using data representative of the U.S. national population. We aggregated annual medical expenditures from the age of diabetes diagnosis to death to determine lifetime medical expenditure. Annual medical expenditures were estimated by sex, age at diagnosis, and diabetes duration using data from 2006-2009 Medical Expenditure Panel Surveys, which were linked to data from 2005-2008 National Health Interview Surveys. We combined survival data from published studies with the estimated annual expenditures to calculate lifetime spending. We then compared lifetime spending for people with diabetes with that for those without diabetes. Future spending was discounted at 3% annually. The discounted excess lifetime medical spending for people with diabetes was $124,600 ($211,400 if not discounted), $91,200 ($135,600), $53,800 ($70,200), and $35,900 ($43,900) when diagnosed with diabetes at ages 40, 50, 60, and 65 years, respectively. Younger age at diagnosis and female sex were associated with higher levels of lifetime excess medical spending attributed to diabetes. Having diabetes is associated with substantially higher lifetime medical expenditures despite being associated with reduced life expectancy. If prevention costs can be kept sufficiently low, diabetes prevention may lead to a reduction in long-term medical costs.


Deciphering neuron-glia compartmentalization in cortical energy metabolism.
Energy demand is an important constraint on neural signaling. Several methods have been proposed to assess the energy budget of the brain based on a bottom-up approach in which the energy demand of individual biophysical processes are first estimated independently and then summed up to compute the brain's total energy budget. Here, we address this question using a novel approach that makes use of published datasets that reported average cerebral glucose and oxygen utilization in humans and rodents during different activation states. Our approach allows us (1) to decipher neuron-glia compartmentalization in energy metabolism and (2) to compute a precise state-dependent energy budget for the brain. Under the assumption that the fraction of energy used for signaling is proportional to the cycling of neurotransmitters, we find that in the activated state, most of the energy ( approximately 80%) is oxidatively produced and consumed by neurons to support neuron-to-neuron signaling. Glial cells, while only contributing for a small fraction to energy production ( approximately 6%), actually take up a significant fraction of glucose (50% or more) from the blood and provide neurons with glucose-derived energy substrates. Our results suggest that glycolysis occurs for a significant part in astrocytes whereas most of the oxygen is utilized in neurons. As a consequence, a transfer of glucose-derived metabolites from glial cells to neurons has to take place. Furthermore, we find that the amplitude of this transfer is correlated to (1) the activity level of the brain; the larger the activity, the more metabolites are shuttled from glia to neurons and (2) the oxidative activity in astrocytes; with higher glial pyruvate metabolism, less metabolites are shuttled from glia to neurons. While some of the details of a bottom-up biophysical approach have to be simplified, our method allows for a straightforward assessment of the brain's energy budget from macroscopic measurements with minimal underlying assumptions.


A comparative study of eicosapentaenoic acid enriched phosphatidylcholine and ethyl ester in improving cognitive deficiency in Alzheimer's disease model rats.
Abundant studies have highlighted the protective effects of docosahexaenoic acid (DHA), in the form of glycerolipids (glycerophosphatides and triglycerides) and DHA-ethyl esters (DHA-EE) in Alzheimer's disease (AD); however, eicosapentaenoic acid (EPA) has rarely been implicated. In the present study, we compared the effects of dietary EPA in the form of phosphatidylcholine (EPA-PC) and EE with DHA-EE (DHA/EPA = 60 mg kg-1 d-1, i.g., 20 days) on cognitive deficits in AD rats. EPA-PC, rather than EPA-EE, significantly improved Aβ-induced cognitive impairment and has a comparable effect with DHA-EE. Further research indicated that EPA-PC and DHA-EE could significantly decrease lipid peroxidation levels, alleviate mitochondria-dependent apoptosis, and inhibit the hyperphosphorylation of tau mediated by GSK3β. These findings suggest that EPA in the form of phosphatidylcholine rather than an ethyl ester has a comparable effect with DHA in improving cognitive impairment in Aβ1-42-induced AD rats.


Impact of Mental Disorders on Employment and Receipt of Public Assistance: An Instrumental Variables Approach.
Unlike other disorders, much of the economic burden of mental disorders is not due to direct costs of care, but due to indirect costs such as loss of employment and the receipt of public assistance. The goal of this paper is to estimate how having a mental disorder impacts employment outcomes, receipt of public assistance and food assistance. We estimate the impact of having a mental disorder on employment and the receipt of public assistance using instrumental variable (IV) methods and a longitudinal dataset: National Epidemiologic Survey on Alcohol and Related Conditions. Having a mental disorder is instrumented by whether the individual has any close family members with a history of alcohol, drug or behavioral disorders. We use bivariate probit models that control for individual socio-demographic characteristics and health status variables. Results show that having any mental disorders is associated with a significant reduction in the probability of being employed by 0.09 (or 9 percentage points), and in the probability of being employed full-time by 0.10. For public assistance outcomes, having any mental disorders is associated with a significant increase in the probability of receiving public assistance and food assistance by 0.10 and 0.15, respectively. These estimated marginal effects using instrumental variable methods are greater than the standard probit model estimates for all outcomes, implying that the true impact of having a mental disorder is underestimated by standard models that do not employ an identifying strategy that controls for endogeneity. The relatively large marginal effects on employment and public assistance suggest that effective diagnosis and treatment of individuals with mental disorders in the workforce can have a significant impact on productivity and public assistance programs.


Association of Walnut Consumption with Total and Cause-Specific Mortality and Life Expectancy in U.S. Adults.
Walnut consumption is associated with health benefits. We aimed to (1) examine the association between walnut consumption and mortality and (2) estimate life expectancy in relation to walnut consumption in U.S. adults. We included 67,014 women of the Nurses' Health Study (1998-2018) and 26,326 men of the Health Professionals Follow-up Study (1998-2018) who were free of cancer, heart disease, and stroke at baseline. We used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During up to 20 years of follow-up, we documented 30,263 deaths. The hazard ratios for total mortality across categories of walnut intake (servings/week), as compared to non-consumers, were 0.95 (95% confidence interval (CI), 0.91, 0.98) for <1 serving/week, 0.94 (95% CI, 0.89, 0.99) for 1 serving/week, 0.87 (95% CI, 0.82, 0.93) for 2-4 servings/week, and 0.86 (95% CI, 0.79, 0.93) for >=5 servings/week (p for trend <0.0001). A greater life expectancy at age 60 (1.30 years in women and 1.26 years in men) was observed among those who consumed walnuts more than 5 servings/week compared to non-consumers. Higher walnut consumption was associated with a lower risk of total and CVD mortality and a greater gained life expectancy among U.S. elder adults.


Involvement of ExbB and TonB in transport across the outer membrane of Escherichia coli: phenotypic complementation of exb mutants by overexpressed tonB and physical stabilization of TonB by ExbB.
The exb locus in Escherichia coli consists of two genes, termed exbB and exbD. Exb functions are related to TonB function in that most TonB-dependent processes are enhanced by Exb. Like tonB mutants, exb mutants were resistant to colicin M and albomycin but, in contrast to tonB mutants, showed only reduced sensitivity to colicins B and D. Overexpressed tonB on the multicopy vector pACYC177 largely restored the sensitivity of exb mutants to colicins B, D, and M but only marginally increased sensitivity to albomycin. Suppression of the btuB451 mutation in the structural gene for the vitamin B12 outer membrane receptor protein by a mutation in tonB occurred only in an exb+ strain. Degradation of the unstable overproduced TonB protein was prevented by overproduced ExbB protein. The ExbB protein also stabilized the ExbD protein. Pulse-chase experiments with radiolabeled ferrichrome revealed release of ferrichrome from exbB, tonB, and fhuC mutants, showing that ferrichrome had not crossed the cytoplasmic membrane. It is concluded that the ExbB and ExbD proteins contribute to the activity of TonB and, like TonB, are involved in receptor-dependent transport processes across the outer membrane.


Mind bomb-2 is an E3 ligase that ubiquitinates the N-methyl-D-aspartate receptor NR2B subunit in a phosphorylation-dependent manner.
The N-methyl-D-aspartate receptor (NMDAR) plays a critical role in synaptic plasticity. Post-translational modifications of NMDARs, such as phosphorylation, alter both the activity and trafficking properties of NMDARs. Ubiquitination is increasingly being recognized as another post-translational modification that can alter synaptic protein composition and function. We identified Mind bomb-2 as an E3 ubiquitin ligase that interacts with and ubiquitinates the NR2B subunit of the NMDAR in mammalian cells. The protein-protein interaction and the ubiquitination of the NR2B subunit were found to be enhanced in a Fyn phosphorylation-dependent manner. Immunocytochemical studies reveal that Mind bomb-2 is localized to postsynaptic sites and colocalizes with the NMDAR in apical dendrites of hippocampal neurons. Furthermore, we show that NMDAR activity is down-regulated by Mind bomb-2. These results identify a specific E3 ubiquitin ligase as a novel interactant with the NR2B subunit and suggest a possible mechanism for the regulation of NMDAR function involving both phosphorylation and ubiquitination.


Longer Screen Vs. Reading Time is Related to Greater Functional Connections Between the Salience Network and Executive Functions Regions in Children with Reading Difficulties Vs. Typical Readers.
An adverse relationship between screen exposure time and brain functional/structural connectivity was reported in typically developing children, specifically related to neurobiological correlates of reading ability. As children with reading difficulties (RD) suffer from impairments in reading and executive functions (EF), we sought to determine the association between the ratio of screen time duration to reading time duration and functional connectivity of EF networks to the entire brain in children with RD compared to typical readers (TRs) using resting state data. Screen/reading time ratio was related to reduced reading and EF abilities. A larger screen/reading time ratio was correlated with increased functional connectivity between the salience network and frontal-EF regions in children with RD compared to TRs. We suggest that whereas greater screen/reading time ratio is related to excessive stimulation of the visual processing system in TRs, it may be related to decreased efficiency of the cognitive control system in RDs.


Wegener granulomatosis presenting as an infiltrative retropharyngeal mass with syncope and hypoglossal paresis.
We describe a woman who presented with syncopal episodes and unilateral hypoglossal paresis in association with a highly infiltrative retropharyngeal mass. After an extensive malignancy workup, the patient was found to have Wegener granulomatosis (WG), an autoimmune necrotizing vasculitis that presents with inflammatory lesions anywhere in the respiratory tract and variable renal involvement. The archetypal presentation in the head and neck is erosive sinonasal crusting, though otologic, pharyngeal, and laryngeal findings are common. Highly uncharacteristic lesions are occasionally encountered and may contribute to significant diagnostic dilemmas. Neurologic involvement is not uncommon, but few reports of hypoglossal paresis and no reports of syncope as a result of WG are found in a review of the literature. Given the variability of presentation of WG in the head and neck, the otolaryngologist must maintain a high degree of suspicion for this disease in the evaluation of airway lesions.


Perceived barriers to medication adherence remain stable following solid organ transplantation.
Perceived barriers to adherence have previously been investigated in SOT to identify plausible intervention targets to improve adherence and transplant outcomes. Fifteen centers in CTOTC enrolled patients longitudinally. Patients >8 years completed Adolescent Scale(AMBS) at two visits at least 6 months apart in the first 17 months post-transplant while their guardians completed PMBS. Differences over time for pre-identified AMBS/PMBS factors were analyzed. Perceived barrier reporting impact on subsequent TAC levels was assessed. A total of 123 patients or their guardians completed PMBS or AMBS. Twenty-six were 6-11 years and 97 were ≥12. The final cohort consisted of kidney (66%), lung (19%), liver (8%), and heart (7%) recipients. Unadjusted analysis showed no statistically significant change in reported barriers from visit 1 (median 2.6 months, range 1.2-3.7 post-transplant) to visit 2 (median 12, range 8.9-16.5). Of 102 patients with TAC levels, 74 had a single level reported at both visits. The factor of "Disease frustration" was identified through the PMBS/AMBS questions about fatigue around medication and disease. Each point increase in "disease frustration" at visit 1 on the AMBS/PMBS doubled the odds of a lower-than-threshold TAC level at visit 2. No clear change in overall level of perceived barriers to medication adherence in the first year post-transplant was seen in pediatric SOT. However, disease frustration early post-transplant was associated with a single subtherapeutic TAC levels at 12 months. A brief screening measure may allow for early self-identification of risk.


Effect of pH, temperature and surface contact on the elaboration of fimbriae and flagella by Salmonella serotype Enteritidis.
Survival of enteric pathogens exposed to various environmental stresses depends upon a number of protective responses, some of which are associated with induction of virulence determinants. Flagella and fimbriae are putative virulence determinants of Salmonella spp. and ELISAs specific for the detection of flagella and SEF21, SEF14 and SEF17 fimbriae were used to assess the effect of temperature and pH upon their elaboration by isolates of Salmonella serotype Enteritidis in planktonic growth and on the surface of two-dimensional gradient agar plates. For three phage type 4 isolates of Enteritidis of comparative clinical provenance, similar phenotypes for the elaboration of these surface antigens were observed. SEF14 fimbriae were elaborated in planktonic growth at 37 degrees C, but not 20 degrees C, at pH 4.77 and above but not at pH 4.04; whereas on agar gradient plates SEF14 fimbriae were elaborated poorly but with best yields at pH 4.04. SEF17 fimbriae were elaborated in planktonic growth at 20 degrees C, but not at 37 degrees C, at pH 6.18 and above but not at pH 5.09 or below; whereas on agar gradient plates SEF17 fimbriae were elaborated well even at pH 4.65. SEF21 fimbriae were expressed very poorly under all conditions tested. Planktonic growth at 37 degrees C induced least flagella whereas growth at 20 degrees C, and particularly surface growth at lower pH values, induced a 'hyper-flagellate' phenotype. Single colonies allowed to form on gradient agar plates were shown to generate different colonial morphologies which were dependent on initial pH. These results demonstrate that the physicochemical environment is an important determinant of bacterial response, especially the induction of putative virulence factors.


Feasibility of a novel web-based physical activity questionnaire for young children.
Accurate assessment of children's physical activity is critical in determining associations between childhood physical activity and health later in life. We have developed a web-based questionnaire, KidActive-Q, to assess physical activity in early childhood. The feasibility and reproducibility of KidActive-Q were assessed in a sample of 20 children aged 2 to 6 years. The questionnaire was distributed to parents via e-mail on two occasions. The median time required to complete KidActive-Q was 2.5 minutes. All the parents reported that the questionnaire was easy or very easy to fill. The intraclass correlations for test-retest reliability were 0.60 (95% confidence interval: 0.31-0.88) for daily time spent outdoors, and 0.85 (95% confidence interval: 0.72-0.97) for daily time watching television. Our results suggest that KidActive-Q is a user-friendly tool for assessing physical activity in early childhood. To our knowledge, this is the first web-based questionnaire specifically developed for young children.